The present application is generally related to medical devices. More specifically, the present invention relates to stent coatings capable of releasing agents over time. In particular, the present invention includes a blend of two co-polymers adapted to release restenosis-inhibiting agents over a sustained time period.
Vascular disease is a leading cause of death and disability in the developed world. In the United States, more than half of all deaths are due to cardiovascular disease. Atherosclerosis is the most common form of vascular disease and leads to insufficient blood supply to body organs, which can result in hearts attacks, strokes, and kidney failure. Atherosclerosis is a form of vascular injury in which the vascular smooth muscle cells in the artery wall undergo hyperproliferation and invade and spread into the inner vessel lining, which can make the vessels susceptible to complete blockage when local blood clotting occurs. This can lead to death of the tissue served by that artery. In the case of a coronary artery, this blockage can lead to myocardial infarction and death.
Coronary artery blockage can be treated with coronary artery bypass surgery and/or angioplasty. Both procedures may initially appear to be successful, but can be in effect undone by the effect of restenosis, or the recurrence of stenosis after such a treatment. Restenosis is believed to include hyperproliferation of vascular smooth muscle cells. In particular, about one third of patients treated using angioplasty have restenosis and blockage within 6 months after the procedure.
To prevent vessel blockage from restenosis, stents are used. Stents are nominally tubular structures and can have either solid walls or lattice like walls, and can be either balloon expandable or self-expanding. After angioplasty balloon dilatation, the previously constricted vessel is at least temporarily widened. A stent can be delivered on a catheter and expanded in place or allowed to expand in place against the vessel walls. With the stent in place, restenosis may or may not be inhibited, but the probability and/or degree of blockage is reduced due to the structural strength of the stent opposing the inward force of any restenosis. Restenosis may occur over the length of the stent and be at least partially opposed by the stent. Restenosis may also occur past the ends of the stent, where the inward forces of the stenosis are unopposed.
Therapeutic agents to inhibit restenosis have been used with varying success. Taxol, an antimicrotubule agent isolated from the bark of the western Pacific Yew tree, is especially effective in inhibiting some cancers and is believed to be effective in combating restenosis. Systemic administration of Taxol can have undesirable side effects, making local administration a preferred mode of treatment.
Local administration of Taxol may be more effective when carried out over a longer time period, such as a time period at least matching the normal reaction time of the body to the angioplasty. At the same time, it may be desirable to provide an initial high dosage of Taxol over an initial period. Local administration of Taxol over a period of days or even months may be most effective in inhibiting restenosis.
Controlled release of therapeutic agents can utilize various technologies. Devices are known having a monolithic layer or coating incorporating a heterogeneous solution and/or dispersion of an active agent in a polymeric substance, where the diffusion of the agent is rate limiting, as the agent diffuses through the polymer to the polymer-fluid interface and is released into the surrounding fluid. In some devices, a soluble substance is also dissolved or dispersed in the polymeric material, such that additional pores or channels are left after the material dissolves. A matrix device is generally diffusion limited as well, but with the channels or other internal geometry of the device also playing a role in releasing the agent to the fluid. The channels can be pre-existing channels or channels left behind by released agent or other soluble substances.
Erodible or degradable devices typically have the active agent physically immobilized in the polymer. The active agent can be dissolved and/or dispersed throughout the polymeric material. The polymeric material is often hydrolytically degraded over time through hydrolysis of labile bonds, allowing the polymer to erode into the fluid, releasing the active agent into the fluid. Hydrophilic polymers have a generally faster rate of erosion relative to hydrophobic polymers. Hydrophobic polymers are believed to have almost purely surface diffusion of active agent, having erosion from the surface inwards. Hydrophilic polymers are believed to allow water to penetrate the surface of the polymer, allowing hydrolysis of labile bonds beneath the surface, which can lead to homogeneous or bulk erosion of polymer.
What would be desirable is a stent coating capable of releasing a therapeutic agent over a sustained time period. What would be advantageous is a stent coating able to release an agent over approximately the same time period as the need for the therapeutic agent. A method for controlling the dosage rate and period of an active agent by controlling the composition of a stent coating would also be advantageous.
The present invention includes a stent having a stent body, a coating disposed over at least a portion of the body, and an active agent releasably dispersed in at least part or portion of the coating. A preferred active agent is paclitaxel, analogues, derivatives, and combinations thereof. The coating can include a blend of a first co-polymer having a first, high release rate and a second co-polymer having a second, lower release rate relative to the first release rate. The first and second copolymers are preferably erodible or biodegradable. In one embodiment, the first copolymer is more hydrophilic than the second copolymer. In one embodiment, the first copolymer includes a polylactic acid/polyethylene oxide (PLA-PEO) copolymer and the second copolymer includes a polylactic acid/polycaprolactone (PLA-PCL) copolymer.
The relative amounts and dosage rates of active agent delivered over time can be controlled by controlling the relative amounts of the faster releasing polymers relative to the slower releasing polymers. For higher initial release rates the proportion of faster releasing polymer can be increased relative to the slower releasing polymer. If most of the dosage is desired to be released over a long time period, most of the polymer can be the slower releasing polymer. The stent can be coated by spraying the stent with a solution or dispersion of polymer, active agent, and solvent. The solvent can be evaporated, leaving a coating of polymer and active agent. The active agent can be dissolved and/or dispersed in the polymer. In some embodiments, the co-polymers can be extruded over the stent body.
In use, the stent can be put into position in a body vessel such as a coronary vessel after a procedure such as angioplasty. The stent can be left in position, and the erodible or biodegradable coating allowed to degrade. As the polymeric coating degrades, the active agent can absorb into the vessel walls.